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Identifying preclinical Alzheimer´s disease in the community using a panel of biomarkers among individuals with Subjective Memory Complaints

Periodic Reporting for period 1 - IPACBIS (Identifying preclinical Alzheimer´s disease in the community using a panel of biomarkers among individuals with Subjective Memory Complaints)

Reporting period: 2018-03-01 to 2020-02-29

The dementia epidemic is a growing socio-economical problem in developed countries, including those in Europe, mainly due to the ageing population. Alzheimer´s disease (AD), the leading cause of dementia, has currently no prevention or cure. Identifying AD at early stages will likely improve the chances of developing an effective therapy. AD-related changes can be detected in brains of healthy individuals many years before the onset of cognitive decline using biomarkers such as lumbar puncture, magnetic resonance of the brain (MRI) or positron emission tomography (PET) with tracers against amyloid and tau proteins. Testing all elderly healthy individuals in the community would not be feasible neither cost-effective, but interestingly many of them experience Subjective Cognitive Decline (SCD) although show preserved cognition when tested. Although conditions such as drugs, depression, anxiety or lack of sleep may be the underlying cause of SCD, a small percentage of individuals with SCD are in fact experiencing the very initial symptoms of AD. The general aim of the IPACBIS project was to identify which subgroup of individuals with SCD is at risk of developing AD dementia in the future. For that, 200 individuals with SCD from the Fundació ACE Healthy Brain Initiative (FACEHBI) cohort were followed-up yearly during 2y and tested with positron emission tomography with Florbetaben (FBB, a tracer against the amyloid protein), lumbar puncture, optical coherence tomography (OCT) and very sensitive neuropsychological tests at the Fundació ACE in Barcelona, Spain. Specifically, we checked whether retinal thickness measured by OCT at baseline predicted PET-FBB positivity, cognitive worsening and conversion to Mild Cognitive Impairment (MCI) after a 2y follow-up. We additionally investigated the differences in visual care received among individuals with SCD, MCI and dementia evaluated at Fundació ACE Memory Clinic with OCT.
The work carried out during the MSCA fellowship mainly focused on the analysis of retinal thickness measurements quantified by OCT and their interaction with neuropsychological scores, progression of cognitive decline to MCI and brain amyloid uptake by PET-FBB.

First, we analyzed data from 129 participants of the FACEHBI cohort with OCT and PET-FBB at baseline and the 2y follow-up visit. Our data indicated that those SCD individuals who had increased thickness in a particular part of the retina (the inner macula) at the baseline evaluation had a higher probability of presenting with a positive PET-FBB scan both at baseline and after 2y. On the contrary, no retinal thickness measures correlated with neuropsychological scores at baseline or predicted conversion to Mild Cognitive Impairment after 2y (Marquié et al., Alzheimers Res Ther, 2020, accepted for publication).

In a cohort of almost 1000 individuals evaluated at Fundació ACE Memory Clinic, we did not detect significant differences on thickness and volume from two different regions of the retina (disk and macula) among individuals with SCD, amnestic Mild Cognitive Impairment and dementia due to Alzheimer (Sánchez et al. Sci Rep 2018; Sánchez et al. Sci Rep 2020).
We additionally analyzed visual function in a cohort of elderly individuals with SCD (including the FACEHBI cohort), MCI and dementia, and found that those with dementia, compared with the SCD and MCI groups, presented worse visual acuity, used less visual correction and fewer ophthalmological treatments and underwent fewer ocular surgeries. OCT image quality worsened in parallel to cognitive decline, while no group differences in past ophthalmological disorders or abnormal OCT findings were detected (Marquié et al. Sci Rep 2019).

Regarding the exploitation and dissemination of the data, the results derived from the IPACBIS project were highlighted in the host institution’s webpage as well as its social media accounts. The fellow has presented the research results at different scientific meetings (Poster at the 13th Human Amyloid Imaging meeting in Miami, FL on Jan 2019; Oral communication at the Workshop on Brain Imaging in Barcelona on May 2019; Poster at the 14th Human Amyloid Imaging meeting in Miami, FL on Jan 2020) and attended several conference for training in Alzheimer´s biomarkers and OCT. No website has been developed for the project.

Three research articles derived from the IPACBIS project have been published in peer-reviewed journals so far (Marquié et al. Visual impairment in aging and cognitive decline: experience in a Memory Clinic. Sci Rep. 2019 Jun 18;9(1):8698, doi: 10.1038/s41598-019-45055-9; and Sanchez et al., Evaluation of macular thickness and volume tested by optical coherence tomography as biomarkers for Alzheimer’s disease in a memory clínic. Sci Rep. 2020 Jan 31;10(1):1580, doi: 10.1038/s41598-020-58399-4; M Marquié et al. Association between retinal thickness and β-amyloid brain accumulation in individuals with Subjective Cognitive Decline: Fundació ACE Healthy Brain Initiative,Alzheimers Res Ther 2020 Mar 31;12(1):37. doi: 10.1186/s13195-020-00602-9).

Regarding communication of the IPACBIS project’s results to society, the fellow has participated in multiple activities such as talks in a library, a seminar for retired high school teachers, a seminar for primary care physicians and a lecture for 5th year medical students, among others. Furthermore, the Communication Department at Fundació ACE, the host institution, has posted several articles highlighting the MSCA fellowship and the published papers in multiple Spanish online general media.
OCT scans have been used in the ophthalmology field for many years to diagnose and monitor common retinal disorders such as open-angle glaucoma, age-related macular degeneration and diabetic retinopathy. In the past few years there has been a growing interest in the neurology field on OCT as a cheap, fast and non-invasive biomarker for neurologic disorders, including multiple sclerosis, Parkinson disease and AD. With the IPACBIS project we investigated the potential usefulness of retinal thickness measurements using OCT as a biomarker of preclinical Alzheimer´s disease in individuals with SCD. Our results suggest that changes in retinal thickness are already present in SCD individuals and relate to brain amyloid load but, at the two-year time-point, not to changes in neuropsychological test scores or conversion to MCI. If further research confirms and deepens the knowledge initiated here, OCT could become a biomarker for the pre-screening of asymptomatic individuals with brain amyloidosis in Primary Care Centers or Memory Clinics. Another important aspect investigated within the IPACBIS project was the worse visual care that patients with dementia received compared to those with MCI and SCD. This finding highlights the need to take care of sensory disturbances in patients with dementia in order to alleviate their symptoms and decrease the burden of their caregivers.
Fundación ACE webpage project descripción